EP0107120B1 - Substituted aminoalcanol phospholipids and process for their preparation - Google Patents

Description

The present invention relates to new substituted aminoalkanol phospholipids and processes for their preparation.

worin X ein Sauerstoff- oder Schwefelatom und Y den Rest-NR¹R² oder-OR³ bedeuten, wobei R¹, R² gleich oder voneinander verschieden sein können und einen gesättigten oder ungesättigten, geradkettigen oder verzweigten Alkylrest mit 1-20 Kohlenstoffatomen, einen Benzylrest, Phenylrest oder Wasserstoff darstellen, und R³ für Phenyl, Benzyl oder C_1-4-Alkyl steht. R⁴, R⁵, R⁶ können gleich oder voneinander verschieden sein und stehen für Wasserstoff oder einen niederen Alkylrest mit 1-4 Kohlenstoffatomen. 1 bedeutet eine ganze Zahl von 0-19, m eine ganze Zahl von 2-6, n eine ganze Zahl von 2-4.The compounds according to the invention correspond to the general formula

in which X is an oxygen or sulfur atom and Y is the radical NR ¹ R ² or -OR ³ , where R ¹ , R ^{2 can be} identical or different and a saturated or unsaturated, straight-chain or branched alkyl radical having 1-20 carbon atoms, represent a benzyl radical, phenyl radical or hydrogen, and R ^{3 represents} phenyl, benzyl or C _1-4 alkyl. R ⁴ , R ⁵ , R ⁶ can be the same or different and stand for hydrogen or a lower alkyl radical with 1-4 carbon atoms. 1 means an integer from 0-19, m an integer from 2-6, n an integer from 2-4.

• 2-(3-Hexadecyl-1-methylureido)-ethanol-phosphocholin
• 2-(1-Methyl-3-octadecylureido)-ethanol-phosphocholin
• 2-(3-Eicosyl-1-methylureido)-ethanol-phosphocholin
• 2-(1-Methyl-3-oleylureido)-ethanol-phosphocholin
• 2-(3-Methyl-1-undecylureido)-ethanol-phosphocholin
• 2-(3-Ethyl-1-undecylureido)-ethanol-phosphocholin
• 2-(3,3-Dimethyl-1-undecylureido)-ethanol-phosphocholin
• 2-(3-Methyl-1-undecylthioureido)-ethanol-phosphocholin
• 2-(1-Hexadecyl-3-methylureido)-ethanol-phosphocholin
• 2-(3-Ethyl-1-hexadecylureido)-ethanol-phosphocholin
• 2-(1-Hexadecyl-3-methylthioureido)-ethanol-phosphocholin
• 2-(3,3-Dimethyl-1-hexadecylureido)-ethanol-phosphocholin
• 2-(3-Methyl-1-octadecylureido)-ethanol-phosphocholin
• 2-(3-Ethyl-1-octadecylureido)-ethanol-phosphocholin
• 2-(3,3-Dimethyl-1-octadecylureido)-ethanol-phosphocholin
• 2-(3-Methyl-1-octadecylthioureido)-ethanol-phosphocholin
• 2-(3-Butyl-1-octadecylureido)-ethanol-phosphocholin
• 2-(3-Hexadecyl-1-octadecylureido)-ethanol-phosphocholin
• 2-(3-Benzyl-1-octadecylureido)-ethanol-phosphocholin
• 3-(3-Methyl-1-octadecylureido)-propanol-(1 )-phosphocholin
• 3-(3-Ethyl-1-octadecylureido)-propanol-(1 )-phosphocholin
• 3-(3,3-Dimethyl-1-octadecylureido)-propanol-(1 )-phosphocholin
• 3-(3-Methyl-1-octadecylthioureido)-propanol-(1 )-phosphochloin
• 4-(3-Methyl-1-octadecylureido)-butanol-(1 )-phosphocholin
• 4-(3-Ethyl-1-octadecylureido)-butanol-(1 )-phosphocholin
• 4-(3,3-Dimethyl-1-octadecylureido)-butanol-(1 )-phosphocholin
• 4-(3-Methyl-1-octadecylthioureido)-butanol-(1 )-phosphocholin
• 2-(1-Eicosyl-3-methylureido)-ethanol-phosphocholin
• 2-(1-Eicosyl-3-ethylureido)-ethanol-phosphocholin
• 2-(3,3-Dimethyl-1-eicosylureido)-ethanol-phosphocholin
• 2-(1-Eicosyl-3-methylthioureido)-ethanol-phosphocholin
• 2-(3-Phenyl-1-undecylureido)-ethanol-phosphocholin
• 2-(3-Benzyl-1-undecylureido)-ethanol-phosphocholin
• 2-(1-Undecylureido)-ethanol-phosphocholin 2-(3-Hexadecyl-1-undecylureido)-ethanol-phosphocholin
• 2-(3-Oleyl-1-undecylureido)-ethanol-phosphocholin
• (2-(3-Methyl-1-octadecylureido)-ethyl]-(2-tri- ethylammonioethyl)-phosphat
• [2-(3-Methyl-1-octadecylureido)-ethyl]-(2-di- methylammonioethyl)-phosphat
• N-Benzyloxycarbonyl-N-methyl-2-aminoethanol-(1 )-phosphocholin
• N-Benzyloxycarbonyl-N-undecyl-2-aminoethanol-(1 )-phosphocholin
• N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethanol-(1 )-phosphocholin
• N-Benzyloxycarbonyl-N-octadecyl-2-aminoethanol-(1 )-phosphocholin
• N-Benzylocycarbonyl-N-octadecyl-3-aminopro- panol-(1 )-phosphocholin
• N-Benzyloxycarbonyl-N-Octadecyl-4-aminobutanol-(1 )-phosphocholin
• N-Benzyloxycarbonyl-N-eicosyl-2-aminoethanol-(1 )-phosphocholin
• N-Methoxycarbonyl-N-octadecyl-2-aminoethanol-(1 )-phosphocholin
• N-Ethoxycarbonyl-N-octadecyl-2-aminoethanol-(1 )-phosphocholin.

Compounds according to the invention are, for example:

• 2- (3-hexadecyl-1-methylureido) ethanol phosphocholine
• 2- (1-methyl-3-octadecylureido) ethanol phosphocholine
• 2- (3-eicosyl-1-methylureido) ethanol phosphocholine
• 2- (1-methyl-3-oleylureido) ethanol phosphocholine
• 2- (3-methyl-1-undecylureido) ethanol phosphocholine
• 2- (3-ethyl-1-undecylureido) ethanol phosphocholine
• 2- (3,3-Dimethyl-1-undecylureido) ethanol phosphocholine
• 2- (3-methyl-1-undecylthioureido) ethanol phosphocholine
• 2- (1-Hexadecyl-3-methylureido) ethanol phosphocholine
• 2- (3-ethyl-1-hexadecylureido) ethanol phosphocholine
• 2- (1-Hexadecyl-3-methylthioureido) ethanol phosphocholine
• 2- (3,3-Dimethyl-1-hexadecylureido) ethanol phosphocholine
• 2- (3-methyl-1-octadecylureido) ethanol phosphocholine
• 2- (3-ethyl-1-octadecylureido) ethanol phosphocholine
• 2- (3,3-Dimethyl-1-octadecylureido) ethanol phosphocholine
• 2- (3-methyl-1-octadecylthioureido) ethanol phosphocholine
• 2- (3-butyl-1-octadecylureido) ethanol phosphocholine
• 2- (3-Hexadecyl-1-octadecylureido) ethanol phosphocholine
• 2- (3-benzyl-1-octadecylureido) ethanol phosphocholine
• 3- (3-methyl-1-octadecylureido) propanol (1) phosphocholine
• 3- (3-ethyl-1-octadecylureido) propanol (1) phosphocholine
• 3- (3,3-Dimethyl-1-octadecylureido) propanol (1) phosphocholine
• 3- (3-methyl-1-octadecylthioureido) propanol (1) phosphochloin
• 4- (3-methyl-1-octadecylureido) butanol (1) phosphocholine
• 4- (3-ethyl-1-octadecylureido) butanol (1) phosphocholine
• 4- (3,3-dimethyl-1-octadecylureido) butanol (1) phosphocholine
• 4- (3-methyl-1-octadecylthioureido) butanol (1) phosphocholine
• 2- (1-eicosyl-3-methylureido) ethanol phosphocholine
• 2- (1-eicosyl-3-ethylureido) ethanol phosphocholine
• 2- (3,3-Dimethyl-1-eicosylureido) ethanol phosphocholine
• 2- (1-eicosyl-3-methylthioureido) ethanol phosphocholine
• 2- (3-phenyl-1-undecylureido) ethanol phosphocholine
• 2- (3-benzyl-1-undecylureido) ethanol phosphocholine
• 2- (1-Undecylureido) ethanol phosphocholine 2- (3-Hexadecyl-1-undecylureido) ethanol phosphocholine
• 2- (3-oleyl-1-undecylureido) ethanol phosphocholine
• (2- (3-methyl-1-octadecylureido) ethyl] - (2-triethylammonioethyl) phosphate
• [2- (3-methyl-1-octadecylureido) ethyl] - (2-dimethylammonioethyl) phosphate
• N-benzyloxycarbonyl-N-methyl-2-aminoethanol (1) phosphocholine
• N-benzyloxycarbonyl-N-undecyl-2-aminoethanol- (1) -phosphocholine
• N-benzyloxycarbonyl-N-hexadecyl-2-aminoethanol- (1) -phosphocholine
• N-benzyloxycarbonyl-N-octadecyl-2-aminoethanol (1) phosphocholine
• N-Benzylocycarbonyl-N-octadecyl-3-aminopropanol (1) phosphocholine
• N-benzyloxycarbonyl-N-octadecyl-4-aminobutanol (1) phosphocholine
• N-benzyloxycarbonyl-N-eicosyl-2-aminoethanol (1) phosphocholine
• N-methoxycarbonyl-N-octadecyl-2-aminoethanol (1) phosphocholine
• N-ethoxycarbonyl-N-octadecyl-2-aminoethanol (1) phosphocholine.

The compounds according to the invention are very biologically active and can be used, for example, in pharmaceuticals and in crop protection the. The new compounds show a strong pharmacological effect, in particular they have a hypotensive and immunoregulatory effect. They can therefore be used to treat high pressure, but also to treat inflammatory diseases and to treat atherosclerosis and tumors. In the structure-like compounds of JP-A-55118494 and JP-A-56 115 792, only an antitumor effect was found.

worin und m die in Formel angegebene Bedeutung besitzen, in einem indifferenten organischen Lösungsmittel, wie z.B. Ether, Tetrahydrofuran, Dioxan, Aceton, Chloroform, Dimethylformamid mit einem Benzylhalogenid oder Chlorameisensäurebenzylester, bevorzugt in Gegenwart einer Hilfsbase, wie z.B. Pyridin, Dimethylaminopyridin, Triethylamin, Alkalihydroxid, Erdalkalioxid, zu den Verbindungen der allgemeinen Formel lll umgesetzt.To produce the new ureidoalkylphospholipids, N-alkylaminoalkanols of the general formula II

in which and m have the meaning given in the formula, in an inert organic solvent such as ether, tetrahydrofuran, dioxane, acetone, chloroform, dimethylformamide with a benzyl halide or benzyl chloroformate, preferably in the presence of an auxiliary base such as pyridine, dimethylaminopyridine, triethylamine, alkali metal hydroxide , Alkaline earth oxide, converted to the compounds of general formula III.

The reaction can also be carried out in two phases, if necessary using a phase transfer catalyst. The compounds III with R ⁷ = benzyl and m = 2 can also be prepared from N-benzylalkylamines and ethylene oxide. The compounds II are accessible either by reacting the corresponding amines with ethylene oxide or by reducing N-acyl-ω-aminoalkanols.

worin I und m die in Formel l angegebenen Bedeutungen besitzen und R⁷ einen durch Hydrierung abspaltbaren Rest, wie z.B. Benzyl oder Benzyloxycarbonyl darstellt, werden nach an sich bekannten Verfahren in die Phospholipide der allgemeinen Formel IV

worin R4, R5, R6, 1, m und n die in Formel 1 und R⁷ die in Formel lll angegebene Bedeutung besitzen, überführt. Verbindungen der Formel IV mit R^{7 =} Benzyloxycarbonyl entsprechen Verbindungen der Formel 1 mit R^{3 =} Benzyl.The compounds of the general formula III

wherein I and m have the meanings given in formula I and R ^{7 is} a radical which can be split off by hydrogenation, such as, for example, benzyl or benzyloxycarbonyl, are converted into the phospholipids of the general formula IV by processes known per se

wherein R4, R5, R6, 1, m and n have the meaning given in formula 1 and R ⁷ as defined in formula III. Compounds of formula IV with R ^{7 =} benzyloxycarbonyl correspond to compounds of formula 1 with R ^{3 =} benzyl.

worin n die in Formel I angegebene Bedeutung hat und Hal ein Chlor- oder Bromatom ist, in einem indifferenten organischen Lösungsmittel, ggfs unter Anwendung einer Hilfsbase, phosphorylieren und nachfolgend durch Reaktion mit einem Amin der Formel VI

worin R4, R5, R6 die in Formel angegebenen Bedeutungen besitzen, in einem indifferenten organischen Lösungsmittel, ggfs unter Druck, zu den Verbindungen der Formel IV umsetzen [H.K. Mangold, Angew. Chem. 91, 550-560 (1979); H. Eibl, Chem. and Phys. of Lipids 26, 405-429, (1980)].For example, the compounds III with dichlorophosphoric acid-cu-haloalkyl esters of the formula V

wherein n has the meaning given in formula I and Hal is a chlorine or bromine atom, phosphorylate in an inert organic solvent, if appropriate using an auxiliary base, and subsequently by reaction with an amine of the formula VI

in which R4, R5, R6 have the meanings given in the formula, in an inert organic solvent, if appropriate under pressure, to give the compounds of the formula IV [HK Mangold, Angew. Chem. 91, 550-560 (1979); H. Eibl, Chem. And Phys. of Lipids 26, 405-429, (1980)].

worin I, m, n und R⁷ die in Formel IV angegebenen Bedeutungen besitzen, umsetzt [H. Eibl, Phospholipid Synthesis in Knight (Herausgeber), Liposomes, Elsevier 1981, S. 19-50].The compounds of the formal IV can also be prepared by using compounds of the formula III with phosphorus oxytrichloride and subsequently with an alkanediol of the formula VII HO- (CH ₂ ) _n -OH VII in which n has the meaning given in formula I, if appropriate using from auxiliary bases, such as triethylamine, and use of inert solvents, such as tetrahydrofuran, to give cyclic intermediates of the formula VIII

wherein I, m, n and R ^{7 have} the meanings given in formula IV, implemented [H. Eibl, Phospholipid Synthesis in Knight (Editor), Liposomes, Elsevier 1981, pp. 19-50].

worin n die in Formel I angegebene Bedeutung hat, in einem indifferenten organischen Lösungsmittel unter Zusatz einer Hilfsbase umsetzt [N.S. Chandrakumar et al., Tetrahedron Lett. 23, 1043-46, (1982); Biochim. Biophys. Acta 711, 357-360, (1982)].The intermediates of formula VIII can also be prepared by compounds of formula III with a cyclic phosphorus compound of formal IX

where n has the meaning given in formula I, in an inert organic solvent with the addition of an auxiliary base [NS Chandrakumar et al., Tetrahedron Lett. 23, 1043-46, (1982); Biochim. Biophys. Acta 711, 357-360, (1982)].

The intermediates VIII can be easily introduced into the compound, for example by treatment with an amine of the formula VI in an organic solvent, if appropriate under pressure gen IV formula (NT Thuong and P. Chabrier, Bull. Soc. Chim. Fr. 1974,667-671).

worin R⁴, R⁵, R⁶, 1, m und n die in Formel l angegebenen Bedeutungen besitzen, entstehen.The compounds of general formula IV are hydrogenated with hydrogen in a suitable organic solvent, such as, for example, methanol, ethanol, ether, dioxane or mixtures thereof with one another and with water, with the benzyl group being split off, in the presence of a customary hydrogenation catalyst, such as, for example, palladium / activated carbon the compounds of the general formula X

wherein R ⁴ , R ⁵ , R ⁶ , 1, m and n have the meanings given in formula I, arise.

worin R¹, R² und X die in Formal I angegebenen Bedeutungen haben, in Substanz oder in einem indifferenten organischen Lösungsmittel, wie z.B. Dimethylformamid, Chloroform, N-Methylacetamid, ggfs unter Zusatz eines Katalysators, wie z.B. Dimethylaminopyridin oder einer Base, wie z.B. Pyridin, Triethylamin, insbesondere bei Verwendung von Verbindungen der Formal XII, zu den erfindungsgemässen Verbindungen der Formel umgesetzt.The compounds of formula X are with carbonic acid derivatives of the formal XI or Xll

wherein R ¹ , R ² and X have the meanings given in formal I, in bulk or in an inert organic solvent, such as dimethylformamide, chloroform, N-methylacetamide, optionally with the addition of a catalyst, such as dimethylaminopyridine or a base, such as Pyridine, triethylamine, in particular when using compounds of the formal XII, converted to the compounds of the formula according to the invention.

The compounds of the formula where R ¹ = R ² = H can expediently be used in aqueous or aqueous-organic media, such as, for example, water / dioxane, using alkali metal cyanates, if appropriate with the addition of an organic or inorganic acid, preferably acetic acid, analogously to the known urea syntheses (see, for example, Weygand-Hilgetag, Org. Chem. Experimentierkunst, Verlag JA Barth-Leipzig 1970, p. 420) from the compounds of formula X.

The compounds of formula I with R ¹ = benzyl and R ² = H and X = 0 in a suitable organic solvent, such as methanol, ethanol, ether, dioxane or mixtures thereof with one another and with water with elimination of the benzyl group in the presence of a Conventional hydrogenation catalyst, such as palladium / activated carbon, are hydrogenated with hydrogen, compounds of the formula I with R ¹ = R ² = H being formed.

To prepare the new (aryl) alkyloxycarbonylaminoalkanol phospholipids of the formula I, N-alkylamino alcohols of the formula II are used in an inert organic solvent, such as e.g. Ether, tetrahydrofuran, dioxane, acetone, chloroform, dimethylformamide with benzyl chloroformate, phenyl chloroformate or alkyl chloroformate, preferably in the presence of an auxiliary base, such as e.g. Pyridine, dimethylaminopyridine, triethylamine, alkali metal hydroxide, alkaline earth metal oxide, converted to the compounds of the general formula XIII.

The compounds of the formula XIII, in which R ³ , I and m have the meanings given in the formula, are converted into the phospholipids of the general formula by processes known per se.

For example, the compounds of the formula XIII can be phosphorylated with dichlorophosphoric acid ca-halogenoalkyl esters of the formula V in an inert organic solvent, if appropriate using an auxiliary base, and subsequently by reaction with an amine of the formula VI in an inert organic solvent, if appropriate Pressure to convert to the compounds of Formula 1.

worin 1, m, n und R³ die in Formel angegebenen Bedeutungen besitzen, umsetzt.The compounds of the formula I can also be prepared by phosphorylating compounds of the formula III with phosphorus oxytrichloride and subsequently with an alkanediol of the formula VII or with compounds of the formula IX, if appropriate, using auxiliary bases such as triethylamine and using inert solvents such as tetrahydrofuran the cyclic intermediates of formula XIV

wherein 1, m, n and R ^{3 have} the meanings given in the formula.

The intermediate products XIV can be easily, e.g. by treatment with an amine of the formula VI, in an organic solvent, if appropriate under pressure, into the compounds of the formula I. The compounds of formula 1 can also be prepared by reacting compounds of formula X with chloroformic acid esters in inert solvents, such as e.g. Chloroform, dimethylformamide, if necessary with the addition of an auxiliary base, e.g. Pyridine, triethylamine.

• 2-Methylamino-ethanol, 2-Ethylamino-ethanol,
• 2-Propylamino-ethanol, 2-Butylamino-ethanol,
• 2-Pentylamino-ethanol, 2-Hexylamino-ethanol,
• 2-Heptylamino-ethanol, 2-Octylamino-ethanol,
• 2-Nonylamino-ethanol, 2-Decylamino-ethanol,
• 2-Undecylamino-ethanol, 2-Dodecylamino-ethanol,
• 2-Tridecylamino-ethanol, 2-Tetradecylaminoethanol,
• 2-Pentadecylamino-ethanol, 2-Hexadecylamino-ethanol,
• 2-Heptadecylamino-ethanol, 2-Octadecylamino-ethanol,
• 2-Nonadecylamino-ethanol,2-Eicosylamino-ethanol,
• 3-Methylamino-propanol, 3-Ethylamino-propanol,
• 3-Propylamino-propanol, 3-Butylamino-propanol,
• 3-Pentylamino-propanol, 3-Hexylamino-propanol,
• 3-Heptylamino-propanol, 3-Octylamino-propanol,
• 3-Nonylamino-propanol, 3-Decylamino-propanol,
• 3-Undecylamino-propanol, 3-Dodecylamino-propanol,
• 3-Tridecylamino-propanol, 3-Tetradecylaminopropanol,
• 3-Pentadecylamino-propanol, 3-Hexadecylamino-propanol,
• 3-Heptadecylamino-propanol, 3-Octadecylamino-propanol,
• 3-Nonadecylamino-propanol,
• 3-Eicosylamino-propanol, 4-Methylamino-butanol,
• 4-Ethylamino-butanol,4-Propylamino-butanol,
• 4-Butylamino-butanol,4-Pentylamino-butanol,
• 4-Hexylamino-butanol, 4-Heptylamino-butanol,
• 4-Octylamino-butanol, 4-Nonylamino-butanol,
• 4-Decylamino-butanol,4-Undecylamino-butanol,
• 4-Dodecylamino-butanol, 4-Tridecylamino-butanol,
• 4-Tetradecylamino-butanol, 4-Pentadecylamino-butanol,
• 4-Hexadecylamino-butanol,4-Heptadecylamino-butanol,
• 4-Nonadecylamino-butanol, 4-Octadecylamino-butanol,
• 4-Eicosylamino-butanol, 5-Methylamino-pentanol,
• 5-Ethylamino-pentanol, 5-Propylamino-pentanol,
• 5-Butylamino-pentanol, 5-Pentylamino-pentanol,
• 5-Hexylamino-pentanol, 5-Heptylamino-pentanol,
• 5-Octylamino-pentanol, 5-Nonylamonio-pentanol,
• 5-Decylamino-pentanol, 5-Undecylamino-pentanol,
• 5-Dodecylamino-pentanol, 5-Tridecylamino-pentanol,
• 5-Tetradecylamino-pentanol, 5-Pentadecylamino-pentanol,
• 5-Hexadecylamino-pentanol, 5-Heptadecylamino-pentanol,
• 5-Octadecylamino-pentanol, 5-Nonadecylamino-pentanol,
• 5-Eicosylamino-pentanol, 6-Methylamino-hexanol,
• 6-Ethylamino-hexanol, 6-Propylamino-hexanol,
• 6-Butylamino-hexanol, 6-Pentylamino-hexanol,
• 6-Hexylamino-hexanol, 6-Heptylamino-hexanol,
• 6-Octylamino-hexanol, 6-Nonylamino-hexanol,
• 6-Decylamino-hexanol, 6-Undecylamino-hexanol,
• 6-Dodecylamino-hexanol, 6-Tridecylamino-hexanol,
• 6-Tetradecylamino-hexanol, 6-Pentadecylamino-hexanol,
• 6-Octadecylamino-hexanol, 6-Hexadecylaminohexanol,
• 6-Heptadecylamino-hexanol, 6-Nonadecylamino-hexanol oder
• 6-Eicosylamino-hexanol

The following compounds are suitable as starting compounds of the formula:

• 2-methylaminoethanol, 2-ethylaminoethanol,
• 2-propylaminoethanol, 2-butylaminoethanol,
• 2-pentylaminoethanol, 2-hexylaminoethanol,
• 2-heptylamino-ethanol, 2-octylamino-ethanol,
• 2-nonylaminoethanol, 2-decylaminoethanol,
• 2-undecylamino-ethanol, 2-dodecylamino-ethanol,
• 2-tridecylaminoethanol, 2-tetradecylaminoethanol,
• 2-pentadecylaminoethanol, 2-hexadecylaminoethanol,
• 2-heptadecylamino-ethanol, 2-octadecylamino-ethanol,
• 2-nonadecylaminoethanol, 2-eicosylaminoethanol,
• 3-methylamino propanol, 3-ethylamino propanol,
• 3-propylamino propanol, 3-butylamino propanol,
• 3-pentylamino propanol, 3-hexylamino propanol,
• 3-heptylamino propanol, 3-octylamino propanol,
• 3-nonylamino propanol, 3-decylamino propanol,
• 3-undecylamino propanol, 3-dodecylamino propanol,
• 3-tridecylamino-propanol, 3-tetradecylaminopropanol,
• 3-pentadecylamino propanol, 3-hexadecylamino propanol,
• 3-heptadecylamino propanol, 3-octadecylamino propanol,
• 3-nonadecylamino propanol,
• 3-eicosylamino-propanol, 4-methylamino-butanol,
• 4-ethylamino-butanol, 4-propylamino-butanol,
• 4-butylamino-butanol, 4-pentylamino-butanol,
• 4-hexylamino-butanol, 4-heptylamino-butanol,
• 4-octylamino-butanol, 4-nonylamino-butanol,
• 4-decylamino-butanol, 4-undecylamino-butanol,
• 4-dodecylamino-butanol, 4-tridecylamino-butanol,
• 4-tetradecylamino-butanol, 4-pentadecylamino-butanol,
• 4-hexadecylamino-butanol, 4-heptadecylamino-butanol,
• 4-nonadecylamino-butanol, 4-octadecylamino-butanol,
• 4-eicosylamino-butanol, 5-methylamino-pentanol,
• 5-ethylamino-pentanol, 5-propylamino-pentanol,
• 5-butylamino-pentanol, 5-pentylamino-pentanol,
• 5-hexylamino-pentanol, 5-heptylamino-pentanol,
• 5-octylamino-pentanol, 5-nonylamino-pentanol,
• 5-decylamino-pentanol, 5-undecylamino-pentanol,
• 5-dodecylamino-pentanol, 5-tridecylamino-pentanol,
• 5-tetradecylamino-pentanol, 5-pentadecylamino-pentanol,
• 5-hexadecylamino-pentanol, 5-heptadecylamino-pentanol,
• 5-octadecylamino-pentanol, 5-nonadecylamino-pentanol,
• 5-eicosylamino-pentanol, 6-methylamino-hexanol,
• 6-ethylamino-hexanol, 6-propylamino-hexanol,
• 6-butylamino-hexanol, 6-pentylamino-hexanol,
• 6-hexylamino-hexanol, 6-heptylamino-hexanol,
• 6-octylamino-hexanol, 6-nonylamino-hexanol,
• 6-decylamino-hexanol, 6-undecylamino-hexanol,
• 6-dodecylamino-hexanol, 6-tridecylamino-hexanol,
• 6-tetradecylamino-hexanol, 6-pentadecylamino-hexanol,
• 6-octadecylamino-hexanol, 6-hexadecylaminohexanol,
• 6-heptadecylamino-hexanol, 6-nonadecylamino-hexanol or
• 6-eicosylamino-hexanol

The starting compounds of formula V are e.g. in question: dichlorophosphoric acid 2-bromo-ethyl ester, dichlorophosphoric acid 2-chloroethyl ester, dichlorophosphoric acid 3-bromopropyl ester, dichlorophosphoric acid 4-bromobutyl ester.

• Dimethylamin, Diethylamin, Dipropylamin, Dibutylamin, Trimethylamin, Triethylamin, Tripropylamin, Tributylamin, Ethylmethylamin, Methylpropylamin, Ethylpropylamin, Butylmethylamin, Butylethylamin,Butylpropylamin,Dimethylethylamin, Butyldimethylamin, Diethylmethylamin, Diethylpropylamin,Butyldiethylamin,Dipro- pylmethylamin,Dipropylethylamin,Butyldipropyl- amin, Dibutylmethylamin, Dibutylethylamin, Dibutylpropylamin, Ethylmethylpropylamin, Butylmethylpropylamin, Butylethylmethylamin, Butylethylpropylamin.

Preferred starting compounds of the formula VI are secondary and tertiary amines, for example:

• Dimethylamine, diethylamine, dipropylamine, dibutylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, ethylmethylamine, methylpropylamine, ethylpropylamine, butylmethylamine, butylethylamine, butylpropylamine, dimethylethylamine, butyldimethylamine, diethylmethylamine, dipylopropylmethylamine, dietylpropylmethylamine, dipylpropylmethylamine, dietylpropylmethylamine, dietylpropylmethylamine, Dibutylethylamine, dibutylpropylamine, ethylmethylpropylamine, butylmethylpropylamine, butylethylmethylamine, butylethylpropylamine.

• Methylisocyanat, Methylisothiocyanat, Ethylisocyanat, Ethylisothiocyanat, Propylisocyanat, Propylisothiocyanat, Isopropylisocyanat, Isopropylisothiocyanat, Butylisocyanat, Butylisothiocyanat, Allylisocyanat, Allylisothiocyanat, Hexylisocyanat, Hexylisothiocyanat, Octiylisocyanat, Octylisothiocyanat, Decylisocyanat, Decylisothiocyanat, Undecylisocyanat, Undecylisothiocyanat, Dodecylisocyanat, Dodecylisothiocyanat, Tetradecylisocyanat, Tetradecylisothiocyanat, Hexadecylisocyanat, Hexadecylisothiocyanat, Octadecylisocyanat, Octadecylisothiocyanat, Oleylisocyanat, Oleylisothiocyanat, Eicosylisocyanat, Eicosylisothiocyanat, Phenylisocyanat, Benzylisocyanat, Phenylisothiocyanat, Benzylisothiocyanat.

Examples of possible starting compounds of the formula XI are:

• Methyl isocyanate, methyl isothiocyanate, ethyl isocyanate, ethyl isothiocyanate, propyl isocyanate, propyl isothiocyanate, isopropyl isocyanate, isopropyl isothiocyanate, butyl isocyanate, butyl isothiocyanate, allyl isocyanate, allyl isothiocyanate, hexyl isocyanate, Hexylisothiocyanat, Octiylisocyanat, Octylisothiocyanat, Decylisocyanat, Decylisothiocyanat, Undecylisocyanat, Undecylisothiocyanat, dodecyl, Dodecylisothiocyanat, tetradecyl isocyanate, Tetradecylisothiocyanat, hexadecyl, Hexadecyl isothiocyanate, octadecyl isocyanate, octadecyl isothiocyanate, oleyl isocyanate, oleyl isothiocyanate, eicosyl isocyanate, eicosyl isothiocyanate, phenyl isocyanate, benzyl isocyanate, phenyl isothiocyanate, benzyl isothiocyanate.

• Dimethylcarbamidsäurechlorid,
• Diethylcarbamidsäurechlorid
• Dipropylcarbamidsäurechlorid,
• Dibutylcarbamidsäurechlorid,
• Methylethylcarbamidsäurechlorid,
• Methylpropylcarbamidsäurechlorid,
• Methylbutylcarbamidsäurechlorid,
• Ethylpropylcarbamidsäurechlorid,
• Butylpropylcarbamidsäurechlorid,
• Butylethylcarbamidsäurechlorid,
• Dimethylthiocarbamidsäurechlorid,
• Diethylthiocarbamidsäurechlorid,
• Dipropylthiocarbamidsäurechlorid,
• Dibutylthiocarbamidsäurechlorid,
• Methylethylthiocarbamidsäurechlorid,
• Methylpropylthiocarbamidsäurechlorid,
• Methylbutylthiocarbamidsäurechlorid,
• Ethylpropylthiocarbamidsäurechlorid,
• Butylpropylcarbamidsäurechlorid,
• Butylethylthiocarbamidsäurechlorid.

The starting compounds of the formula XII are preferably carbamic acid and thiocarbamic acid chlorides, the substituents R ¹ , R ^{2 of} which contain a short-chain hydrocarbon chain with 1-4 C atoms, for example:

• Dimethyl carbamic acid chloride,
• Diethyl carbamic acid chloride
• Dipropylcarbamic acid chloride,
• Dibutylcarbamic acid chloride,
• Methyl ethyl carbamic acid chloride,
• Methylpropylcarbamic acid chloride,
• Methyl butyl carbamic acid chloride,
• Ethyl propyl carbamic acid chloride,
• Butylpropylcarbamic acid chloride,
• Butylethyl carbamic acid chloride,
• Dimethylthiocarbamic acid chloride,
• Diethylthiocarbamic acid chloride,
• Dipropylthiocarbamic acid chloride,
• Dibutylthiocarbamic acid chloride,
• Methylethylthiocarbamic acid chloride,
• Methylpropylthiocarbamic acid chloride,
• Methylbutylthiocarbamic acid chloride,
• Ethyl propylthiocarbamic acid chloride,
• Butylpropylcarbamic acid chloride,
• Butylethylthiocarbamic acid chloride.

The new substituted aminoalkanol phospholipids can e.g. processed into pharmaceutical preparations. The pharmaceutical preparations are those for enteral, oral, rectal and parenteral administration, which contain the active pharmaceutical ingredients alone or together with a customary, pharmaceutically usable carrier material. The pharmaceutical preparation of the active ingredient is advantageously in the form of single doses which are tailored to the desired administration, such as e.g. Tablets, coated tablets, capsules, suppositories, granules, solutions, emulsions or suspensions. The dosage of the compounds is usually between 1-1000 mg per dose, preferably 1-10 mg per dose, and can be administered one or more times, preferably two to three times, daily.

• A. Herstellung der Alkohole der Formel III
  • Beispiel 1
    • N-Benzyloxycarbonyl-N-methyl-2-aminoethanol.
    • 75 g 2- Methylamino -ethanol und 101g Triethylamin werden mit 1000 ml absol. Chloroform gemischt und zu dieser Lösung 171 g Chlorameisensäurebenzylester bei ca. 20°C zugetropft. Die Mischung wird 1 h bei Raumtemperatur gerührt, mit Wasser, verdünnter Salzsäure und nochmals mit Wasser gewaschen und über Natriumsulfat getrocknet. Nach Abdampfen der Lösungsmittel im Vakuum bleiben 173 g Öl zurück. IR (Film): 1695 cm-¹
  • Beispiel 2
    • N-Benzyloxycarbonyl-N-undecyl-2-aminoethanol
      analog Beispiel 1 aus:
      • 124 g 2- Undecylamino -ethanol
      • 58 g Triethylamin
      • 500 ml Chloroform
      • 97 g Chlorameisensäurebenzylester.
    • Reinigung durch Säulenchromatographie (Kieselgel//Hexan/Essigsäureethylester).
    • Ausbeute: 113 g Öl mit IR (Film): 1683 cm^-1
  • Beispiel 3
    • N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethanol
      analog Beispiel 1 aus:
      • 71 g 2-Hexadecylamino-ethanol
      • 25 g Triethylamin
      • 250 ml Chloroform
      • 43 g Chlorameisensäurebenzylester.
    • Reinigung durch Säulenchromatographie (Kieselgel//Chloroform).
    • Ausbeute: 40,2 g Öl mit IR (Film): 1690 cm-¹
  • Beispiel 4
    • N-Benzyl-N-octadecyl-2-aminoethanol.
    • In ein Gemisch aus 65,9 g N-Benzyl-octadecylamin und 200 ml Methanol werden bei Raumtemperatur innerhalb von 2 h 40 ml mit Trockeneis gekühltes Ethylenoxid zugetropft, die Mischung weitere 3 h gerührt, das Lösungsmittel abgezogen und der Rückstand durch Säulenchromatographie (Kieselgel/Chloroform) gereinigt.
    • Ausbeute: 73 g mit Schmp. 31 °C
  • Beispiel 5
    • N-Benzyloxycarbonyl-N-octadecyl-3-amino- propanol
      analog Beispiel 1 aus:
      • 34,2 g 3-Octadecylamino-propanol
      • 10,5 g Triethylamin
      • 100 ml Chloroform
      • 17,7 g Chlorameisensäurebenzylester.
    • Reinigung durch Säulenchromatographie (Kieselgel//Chloroform).
    • Ausbeute: 33,1 g Öl mit IR (Film): 1680 cm-¹
  • Beispiel 6
    • N-Benzyloxycarbonyl-N-octadecyl-4-aminobutanol
      analog Beispiel 1 aus:
      • 24,8 g 4- Octadecylamino -butanol
      • 7,4 g Triethylamin
      • 200 ml Chloroform
      • 12,5 g Chlorameisensäurebenzylester.
    • Reinigung durch Säulenchromatographie (Kieselgel/Chloroform).
    • Ausbeute: 18 g Öl mit IR (Film): 1690 cm^-1
  • Beispiel 7
    • N-Benzyloxycarbonyl-N-eicosyl-2-aminoethanol
      analog Beispiel 1 aus:
      • 32,8 2-Eicosylamino-ethanol
      • 9,7 g Triethylamin
      • 200 ml Chloroform
      • 16,3 g Chlorameisensäurebenzylester.
    • Reinigung durch Säulenchromatographie (Kieselgel//Hexan/Essigsäureethylester).
    • Ausbeute: 14,6g mit Schmp. 53-54°C, IR (Film): 1690 cm^-1
    • Darstellung der Phospholipide der Formel IV.
  • Beispiel 8
    • N-Benzyloxycarbonyl-N-methyl-2-aminoethanol-phosphocholin.
      • a) In eine Mischung von 105g Dichlorphosphorsäure-2-bromethylester, 53 ml Pyridin und 800 ml absol. Chloroform werden 46 g N-Benzyloxycarbonyl-N-methyl-2-aminoethanol, gelöst in 220 ml Chloroform, unter Eiskühlung zugetropft. Die Reaktionsmischung wird 1 h unter Eiskühlung und nach Zugabe von Eiswasser eine weitere Stunde bei Raumtemperatur gerührt. Die organische Phase wird abgetrennt, mit Wasser neutral gewaschen, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wird durch Säulenchromatographie (Kieselgel/Chloroform/ Methanol) gereinigt.
    • Ausbeute: 28g (N-Benzyloxycarbonyl-N-me- tyhl-2-aminoethyl)-2-bromethyl-phosphat (Öl).
      • b) 28 g (N-Benzyloxycarbonyl-N-methyl-2-aminoethyl)-2-bromethylphosphat werden in 300 ml trockenem Toluol gelöst, mit 30 ml 33%iger ethanolischer Trimethylaminlösung versetzt und die Mischung 4 h bei 60°C im Autoklaven gerührt. Anschliessend werden die Lösungsmittel am Rotavapor abgezogen und der Rückstand durch Säulenchromatographie (Kieselgel/Chloroform/ Methanol/Wasser) gereinigt.
    • Ausbeute: 8,5 g mit Schmp. 75-78°C.
  • Beispiel 9
    • N-Benzyloxycarbonyl-N-undecyl-2-aminoethanol-phosphocholin
      analog Beispiel 8 aus:
      • a) 75 g Dichlorphosphorsäure-2-bromethylester
        • 51 ml Pyridin
        • 600 ml Chloroform
        • 54,2 g N-Benzyloxycarbonyl-N-undecyl-2-aminoethanol in 150 ml Chloroform.
    • Ausbeute: 47,8 g (N-Benzyloxycarbonyl-N-undecyl-2-aminoethyl)-2-bromethyl-phosphat (Öl).
      • b) 47,6 g (N-Benzyloxycarbonyl-N-undecyl-2-aminoethyl)-2-bromethyl-phosphat.
        • 300 ml Toluol
        • 30 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute: 29,9 mit Schmp. 224-226°C IR (in KBr): 1692 cm^-1
  • Beispiel 10
    • N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethanol-phosphocholin
      analog Beispiel 8 aus:
      • a) 46 g Dichlorphosphorsäure-2-bromethylester
        • 23 ml Pyridin
        • 400 ml Chloroform
        • 40 g N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethanol in 95 ml Chloroform.
    • Ausbeute: 21,5g (N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethyl)-2-bromethyl-phosphat (Öl).
      • b) 21,4g (N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethyl)-2-bromethyl-phosphat
        • 100 ml Toluol
        • 10 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute: 7 mit Schmp. 226-228°C IR (in KBr): 1691 cm^-1
  • Beispiel 11
    • N-Benzyl-N-octadecyl-2-aminoethanol-phosphocholin.
      • a) In eine Mischung aus 10 g N-Benzyl-N-octadecyl-2-aminoethanol, 50 ml Chloroform und 5 g Triethylamin werden unter Eiskühlung 8,3 g Dichlorphosphorsäure-2-bromethylester eingetropft. Die Reaktionsmischung wird weitere 3 h bei Raumtemperatur und nach Zugabe von Eiswasser nochmals 1 h gerührt. Die organische Phase wird abgetrennt, mit Wasser neutral gewaschen, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wird durch Säulenchromatographie (Kieselgel/Chloroform/Methanol) gereinigt.
    • Ausbeute: 9,2 g (N-Benzyl-N-octadecyl-2-- aminoethyl)-2-bromethylphosphat (Öl)
      • b) N-Benzyl-N-octadecyl-2-aminoethanol- phosphocholin
        • analog Beispiel 8b aus:
        • 9,2 g (N-Benzyl-N-octadecyl-2-aminoethyl)-2- bromethylphosphat
        • 30 ml Toluol
        • 5,2 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute: 6,4 g mit Schmp. 215-217°C.
  • Beispiel 12
    • N-Benzyloxycarbonyl-N-octadecyl-3-amino- propanol-(1)-phosphocholin
      analog Beispiel 8 aus:
      • a) 34,3 g Dichlorphosphorsäure-2-bromethyl- ester
        • 140 ml Pyridin
        • 140 ml Chloroform
        • 32,7 g N-Benzyloxycarbonyl-N-octadecyl-3-aminopropanol in 100 ml Chloroform.
    • Ausbeute: 9,6 g (N-Benzyloxycarbonyl-N-octadecyl-3-aminopropyl)-2-bromethyl-phosphat (Öl).
      • b) 9,5 g (N-Benzyloxycarbonyl-N-octadecyl-3-aminopropyl)-2-bromethyl-phosphat
        • 45 ml Toluol
        • 5 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute: 6,5 g mit Schmp. 219-223°C IR (in KBr): 1688 cm^-1.
  • Beispiel 13
    • N-Benzyloxycarbonyl-N-octadecyl-4-aminobutanol-(1)-phosphocholin
      analog Beispiel 8 aus:
      • a) 17,4g Dichlorphosphorsäure-2-bromethyl- ester
        • 72 ml Pyridin
        • 72 ml Chloroform
        • 17 g N-Benzyloxycarbonyl-N-octadecyl-4-aminobutanol in 40 ml Chloroform.
    • Ausbeute:6,1 g (N-Benzyloxycarbonyl-N-octadecyl-4-aminobutyl)-2-bromethyl-phosphat (Öl).
      • b) 6 g (N-Benzyloxycarbonyl-N-octadecyl-4-aminobutyl)-2-bromethyl-phosphat
        • 30 ml Toluol
        • 3 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute: 4g mit Schmp. 220°C (Zers.) IR (in KBr): 1694 cm^-1.
  • Beispiel 14
    • N-Benzyloxycarbonyl-N-eicosyl-2-aminoethanol-phosphocholin
      analog Beispiel 8 aus:
      • a) 14,5 g Dichlorphosphorsäure-2-bromethyle- ster
        • 7,5 ml Pyridin
        • 120 ml Chloroform
        • 14,5 g N-Benzyloxycarbonyl-N-eicosyl-2-aminoethanol in 30 ml Chloroform.
    • Ausbeute: 12,7 g (N-Benzyloxycarbonyl-N-eicosyl-2-aminoethyl)-2-bromethyl-phosphat (Öl).
      • b) 12.6 g (N-Benzyloxycarbonyl-N-eicosyl-2-aminoethyl)-2-bromethyl-phosphat
        • 60 ml Toluol
        • 20 ml 33%ige ethanolische Trimethylaminlösung.
    • Ausbeute:1 1,4 g mit Schmp. 210°C (Zers.) IR (in KBr): 1694 cm^-1.
  • Beispiel 15
    • (N-Benzyl-N-octadecyl-2-aminoethyl)-2-tri- ethylammonioethylphosphat
      analog Beispiel 8b aus
      • 11,8 g (N-Benzyl-N-octadecyl-2-aminoethyl)-2- bromethyl-phosphat
      • 60 ml Toluol
      • 5 ml Triethylamin und 10 ml 2-Propanol.
    • Ausbeute: 10,2 g mit Schmp. 215-216°C.
  • Beispiel 16
    • (N-Benzyl-n-octadecyl-2-aminoethyl)-2-dimet- hylammonioethylphosphat
      analog Beispiel 8b aus:
      • 11,8g g (N-Benzyl-N-octadecyl-2-aminoethyl)-2- bromethyl-phosphat
      • 60 ml Toluol und 30 ml 2-Propanol
      • 10 ml 40%ige wässrige Dimethylaminlösung.
    • Ausbeute: 9,5 g mit Schmp. 210°C.
• C. Herstellung der Phospholipide der Formel X
  • Beispiel 17
    • 2-Methylamino-ethanol-phosphocholin.
    • 8 g N-Benzyloxycarbonyl-N-methyl-2-aminoethanol-phosphocholin werden in 60 ml Dioxan und 15 ml Wasser gelöst, die Lösung mit 0,8 g 10%iger Palladium-/Aktivkohle versetzt und die Reaktionsmischung mit Wasserstoff hydriert. Nach Ende der H₂-Aufnahme wird die Lösung filtriert und das Filtrat im Vakuum zur Trockene eingeengt.
    • Ausbeute: 5 g wachsartige Substanz.
  • Beispiel 18
    • 2-Undecylamino-ethanol-phosphocholin analog Beispiel 17 aus:
      • 14g N-Benzyloxycarbonyl-N-undecyl-2-aminoethanol-phosphocholin und
      • 1,4g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 9,2 g mit Schmp. 205-208°C.
  • Beispiel 19
    • 2-Hexadecylamino-ethanol-phosphocholin analog Beispiel 17 aus:
      • 6,9 g N-Benzyloxycarbonyl-N-hexadecyl-2-aminoethanol-phosphocholin und
      • 0,7 g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 5,2 g mit Schmp. 203-207°C (Zers.).
  • Beispiel 20
    • 2-Octadecylamino-ethanol-phosphocholin analog Beispiel 17 aus:
      • 6,4 g N-Benzyl-N-octadecyl-2-aminoethanol- phosphocholin und
      • 0,6g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 5 g mit Schmp. 210-212°C.
  • Beispiel 21
    • 3-Octadecylamino-propanoi-phosphocholin analog Beispiel 17 aus:
      • 6,2 g N-Benzylocycarbonyl-N-octadecyl-3-ami- nopropanol-phosphocholin und
      • 0,6g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 4,4 g mit Schmp. 227-229°C.
  • Beispiel 22
    • 4-Octadecylamino-butanol-phosphocholin analog Beispiel 17 aus:
      • 3,7 g N-Benzyloxycarbonyl-N-octadecyl-4-aminobutanol-phosphocholin und
      • 0,4g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 2,2 g mit Schmp. 208-210°C.
  • Beispiel 23
    • 2-Eicosylamino-ethanol-phosphocholin analog Beispiel 17 aus:
      • 11 g N-Benzyloxycarbonyl-N-eicosyl-2-aminoethanol-phosphocholin und
      • 1,1 g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 7,4 g mit Schmp. 214-219°C.
  • Beispiel 24
    • (N-Octadecyl-2-aminoethyl)-2-triethylammo- nioethyl-phosphat
      analog Beispiel 17 aus:
      • 10 g (N-Benzyl-N-octadecyl-2-aminoethyl)-2- triethylammonioethyl-phosphat und
      • 1 g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 8,1 g mit Schmp. 218-219°C.
  • Beispiel 25
    • (N-Octadecyl-2-aminoethyl)-2-dimethylam- monioethyl-phosphat
      analog Beispiel 17 aus:
      • 9,3 g (N-Benzyl-N-octadecyl-2-aminoethyl)-2-di- methylammonioethyl-phosphat und
      • 0,9 g Pd-Aktivkohle in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 7,5 g mit Schmp. 220-223°C.
• D. Herstellung der Phospholipide der Formel
  • Beispiel 26
    • 2-(3-Ethyl-1-octadecylureido)-ethanol-phosphocholin.
    • 0,5 g 2-Octadecylamino-ethanol-phosphocholin werden in 10 ml Chloroform gelöst, die Lösung mit 0,14 g Ethylisocyanat und einigen Tropfen Dimethylformamid versetzt und ca. 4 bei Raumtemperatur gerührt. Die Lösung wird im Vakuum eingeengt und der Rückstand durch Säulenchromatographie (Kieselgel//Chloroform/Methanoi/ Wasser) gereinigt.
    • Ausbeute: 0,43 g mit Schmp. 214-215°C IR (in KBr): 1630, 1535 cm^-1.
  • Beispiel 27
    • 2-(3-Methyl-1-octadecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Octadecylamino-ethanol-phosphocholin
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,35 g mit Schmp. 219-220°C IR (in KBr): 1625,1540 cm^-1.
  • Beispiel 28
    • 2-(3-Metyhl-1-octadecylthioureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Octadecylamino-ethanol-phosphocholin
      • 0,15 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,41 g mit Schmp. 215-217°C.
  • Beispiel 29
    • 2-(3,3-Dimethyl-1-octadecylureido)-ethanol-phosphocholin.
    • 0,5 g 2-Octadecylamino-ethanol-phosphocholin werden in 10 ml Chloroform gelöst, die Lösung mit 0,21 g Dimethylcarbamidsäurechlorid und 0,14g Silbercarbonat versetzt und ca. 12h bei Raumtemperatur gerührt. Die Lösung wird im Vakuum eingeengt und der Rückstand durch Säulenchromatographie (Kieselgel/Chloroform/ Methanol/Wasser) gereinigt.
    • Ausbeute: 0,31 g mit Schmp. 215-216°c IR (in KBr) 1634cm^-1.
  • Beispiel 30
    • 2-(3-Butyl-1-octadecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Octadecylamino-ethanol-phosphocholin
      • 0,2 g Butylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,38 g mit Schmp. 208-210°C IR (in KBr): 1625, 1530 cm^-1.
  • Beispiel 31
    • 2-(3-Hexadecyl-1-octadecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Octadecylamino-ethanol-phosphocholin
      • 0,6 g Hexadecylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,63 g mit Schmp. 200-203°C IR (in KBr): 1625, 1535cm^-1.
  • Beispiel 32
    • 2-(3-Benzyl-1-octadecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Octadecylamino-ethanol-phosphocholin
      • 0,27 g Benzylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,42 g mit Schmp. 221-222°C.
  • Beispiel 33
    • 2-(3-Methyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,15 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,3g wachsartige Substanz mit Klarpunkt~185°C
      • IR (in KBr): 1629, 1540 cm^-1.
  • Beispiel 34
    • 2-(3-Ethyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,18 g Ethylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,3g wachsartige Substanz mit Klarpunkt ~180-183°C
      • IR (in KBr): 1626, 1536 cm^-1.
  • Beispiel 35
    • 2-(3,3-Dimethyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 29 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,28 g Dimethylcarbamidsäurechlorid
      • 0,18 g Silbercarbonat
      • 10 ml Chloroform.
    • Ausbeute: 0,32 wachsartige Substanz mit Klarpunkt: 203-204°C
      • IR (in KBr): 1634cm^-1.
  • Beispiel 36
    • 2-(3-Methyl-1-undecylthioreido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,19 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,33g wachsartige Substanz mit Klarpunkt~165°C.
  • Beispiel 37
    • 2-(3-Phenyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,31 g Phenylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,61 g wachsartige Substanz IR (in KBr): 1649,1538 cm^-1.
  • Beispiel 38
    • 2-(3-Benzyl-1-undecylureido)-ethanol-phosphocholin
    • analog Beispiel 26 aus:
      • 1,5 g 2-Undecylamino-ethanol-phosphocholin
      • 1,1 g Benzylisocyanat
      • 30 ml Chloroform.
    • Ausbeute: 1,7 g wachsartige Substanz IR (in KBr): 1533,1628 cm^-1.
  • Beispiel 39
    • 2-(3-Hexadecyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,7 g Hexadecylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,69 mit Schmp. 196-199°C IR (in KBr): 1622,1533 cm-^i.
  • Beispiel 40
    • 2-(3-Oleyl-1-undecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Undecylamino-ethanol-phosphocholin
      • 0,8 g Oleylisocyanat
      • 10 ml Chloroform unter Stickstoff.
    • Ausbeute: 0,61 g wachsartige Substanz.
  • Beispiel 41
    • 2-(1-Hexadecyl-3-methylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,3 g 2-Hexadecylamino-ethanol-phosphocholin
      • 0,08 g Methylisocyanat
      • 5 ml Chloroform.
    • Ausbeute: 0,22 g mit Schmp. 215-218°C IR (in KBr): 1635, 1540 cm^-1.
  • Beispiel 42
    • 2-(3-Ethyl-1-hexadecylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Hexadecylamino-ethanol-phosphocholin
      • 0,15 g Ethylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,45 g mit Schmp. 213-217°C.
  • Beispiel 43
    • 2-(1-Hexadecyl-3-methylthioureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Hexadecylamino-ethanol-phosphocholin
      • 0,16 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,2 g mit Schmp. 210-212°C.
  • Beispiel 44
    • 2-(3,3-Dimethyl-1-hexadecylureido)-ethanol-phosphocholin
      analog Beispiel 29 aus:
      • 0,3 g 2-Hexadecylamino-ethanol-phosphocholin
      • 0,24 g Dimethylcarbamidsäurechlorid
      • 0,1 g Silbercarbonat
      • 5 ml Chloroform.
    • Ausbeute: 0,15 g mit Schmp. 208-211 °C IR (in KBr): 1635 cm^-1.
  • Beispiel 45
    • 3-(3-Methyl-1-octadecylureido)-propanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 3-Octadecylamino-propanol-(1)-phosphocholin
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,43 g mit Schmp. 221-224°C IR (in KBr): 1628,1540 cm-^i.
  • Beispiel 46
    • 3-(3-Ethyl-1-octadecyiureido)-propanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 3-Octadecylamino-propanol-(1)-phosphocholin
      • 0,14 g Ethylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,3 g mit Schmp. 215-218°C IR (in KBr): 1626, 1535cm^-1.
  • Beispiel 47
    • 3-(3,3-Dimethyl-1-octadecylureido)-propanol-(1)-phosphocholin
      analog Beispiel 29 aus:
      • 0,5 g 3-Octadecylamino-propanol-(1)-phosphocholin
      • 0,18 g Dimethylcarbamidsäurechlorid
      • 0,14 g Silbercarbonat
      • 10 ml Chloroform.
    • Ausbeute: 0,28 g mit Schmp. 224-225°C IR (in KBr): 1633 cm^-1.
  • Beispiel 48
    • 3-(3-Methyl-1-octadecylthioureido)-propanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 3-Octadecylamino-propanol-(1)-phosphocholin
      • 0,15 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,36 g mit Schmp. 210-212°C.
  • Beispiel 49
    • 4-(3-Methyl-1-octadecylureido)-butanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 4-Octadecylamino-butanol-(1)-phosphocholin
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,4 g mit Schmp. 226-230°C IR (in KBr): 1629,1541 cm^-1.
  • Beispiel 50
    • 4-(3-Ethyl-1-octadecylureido)-butanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,3 g 4-Octadecylamino-butanol-(1)-phosphocholin
      • 0,1 g Ethylisocyanat
      • 5 ml Chloroform.
    • Ausbeute: 0,25 g mit Schmp. 215-216°C IR (in KBr): 1623, 1532cm^-1.
  • Beispiel 51
    • 4-(3,3-Dimethyl-1-octadecyl)-butanol-(1)-phosphocholin
      ananolg Beispiel 29 aus:
      • 0,3 g 4-Oxtadecylamino-butanol-(1)-phosphocholin
      • 0,13 g Dimethylcarbamidsäurechlorid
      • 0,1 g Silbercarbonat
      • 5 ml Chloroform.
    • Ausbeute: 0,15 g mit Schmp. 234-236°C IR (in KBr): 1632 cm-'.
  • Beispiel 52
    • 4-(3-Methyl-1-octadecylthioureido)-butanol-(1)-phosphocholin
      analog Beispiel 26 aus:
      • 0,3 g 4-Octadecylamino-butanol-(1)-phosphocholin
      • 0,1 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,21 g mit Schmp. 221-224°C.
  • Beispiel 53
    • 2-(1-Eicosyl-3-methylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Eicosylamino-ethanol-phosphocholin
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,35 g mit Schmp. 222-224°C.
  • Beispiel 54
    • 2-(1-Eicosyl-3-ethylureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Eicosylamino-ethanol-phosphocholin
      • 0,14g Ethylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,4 g mit Schmp. 218-220°C.
  • Beispiel 55
    • 2-(3,3-Dimethyl-1-eicosylureido)-ethanol-phosphocholin
      analog Beispiel 29 aus:
      • 0,5 g 2-Eicosylamino-ethanol-phosphocholin
      • 0,21 g Dimethylcarbamidsäurechlorid
      • 0,14g Silbercarbonat
      • 10 ml Chloroform.
    • Ausbeute: 0,3 g mit Schmp. 215-217°C.
  • Beispiel 56
    • 2-(1-Eicosyl-3-methylthioureido)-ethanol-phosphocholin
      analog Beispiel 26 aus:
      • 0,5 g 2-Eicosylamino-ethanol-phosphocholin
      • 0,15 g Methylisothiocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,3 g mit Schmp. 210-211 °C.
  • Beispiel 57
    • 2-(1-Undecylureido)-ethanol-phosphocholin analog Beispiel 17 aus:
      • 1,2 g 2-(3-Benzyl-1-undecylureida)-ethanol-phosphocholin und
      • 0,72 g Pd-Aktivkohle, die in 6 Portionen innerhalb von 20 h zugegeben werden, in Dioxan/Wasser = 4:1 (V/V).
    • Ausbeute: 0.5 g wachsartige Substanz IR (in KBr): 1652,1597 cm-¹.
  • Beispiel 58
    • [2-(3-Methyl-1-octadecylureido)-ethyl]-(2- triethylammonioethyl)-phosphat
      analog Beispiel 26 aus:
      • 0,5 g (N-Octadecyl-2-aminoethyl)-2-triethylam- monioethyl-phosphat
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform,
    • Ausbuete: 0,41 g mit Schmp. 220-221°C.
  • Beispiel 59
    • [2-(3-Methyl-1-octadecylureido)-ethyl]-(2-di- methylammonioethyl)-phosphat
      analog Beispiel 26 aus:
      • 0,5 g (N-Octadecyl-2-aminoethyl)-2-dimethylam- monioethyl-phosphat
      • 0,11 g Methylisocyanat
      • 10 ml Chloroform.
    • Ausbeute: 0,35 g mit Schmp. 215-216°C.
  • Beispiel 60
    • 2-(3-Nexadecyl-1-methylureido)-ethanol-phosphocholin.
    • 0,5 g 2-Methylamino-ethanol-phosphocholin werden in 10 ml N-Methylacetamid gelöst, die Lösung mit 1,08g Hexadecylisocyanat versetzt und 24h bei Raumtemperatur gerührt. Die Lösung wird im Vakuum eingeengt und der Rückstand durch Säulenchromatographie (Kieselgel// Chloroform/Methanol/Wasser)
    • gereinigt.
    • Ausbeute: 0,3 g mit Schmp. 210-213°C.
    • Analog Beispiel 60 werden hergestellt:
      • 2-(1-Methyl-3-octadecylureido)-ethanol-phosphocholin
      • 2-(3-Eicosyl-1-methylureido)-ethanol-phosphocholin
      • 2-(1-Methyl-3-oleylureido)-ethanol-phosphocholin
  • Beispiel 61
    • N-Methoxycarbonyl-N-octadecyl-2-aminoethanol-(1 )-phosphocholin.
    • 50 mg N-Octadecyl-2-aminoethanol-(1)-phosphocholin werden in 2 ml Chloroform gelöst, 20mg Chlorameisensäuremethylester und 5 Tropfen Triethylamin hinzugefügt. Die Mischung wird eine Stunde bei Raumtemperatur gerührt, im Vakuum eingeengt und der Rückstand durch Säulenchromatographie (Kieselgel//Chloroform/ Methanol/Wasser) gereinigt.
    • Ausbeute: 41 mg wachsartige Substanz IR (in KBr): 1692cm^-1.
  • Beispiel 62
    • N-Ethoxycarbonyl-N-octadecyl-2-aminoethanol-(1 )-phosphocholin
      anaolg Beispiel 61 aus:
      • 50 mg N-Octadecyl-2-aminoethanol-(1)-phosphocholin
      • 20 mg Chlorameisensäureethylester
      • 5 Tropfen Triethylamin
      • in 2 ml Chloroform.
    • Ausbeute: 39 mg wachsartige Substanz IR (in KBr): 1690 cm^-1.
  • Beispiel 63
    • N-Benzyloxycarbonyl-N-octadecyl-2-aminoethanol-(1)-phosphocholin analog Beispiel 61 aus:
      • 50 mg N-Octadecyl-2-aminoethanol-(1)-phosphocholin
      • 34 mg Chlorameisensäurebenzylester
      • 5 Tropfen Triethylamin
      • in 2 ml Chloroform.
    • Ausbeute: 55 mg mit Schmp. 211 °C.

The preparation of the compounds according to the invention is explained in more detail by the following examples:

• A. Preparation of the alcohols of the formula III
  • example 1
    • N-benzyloxycarbonyl-N-methyl-2-aminoethanol.
    • 75 g of 2-methylaminoethanol and 101g of triethylamine are absolute with 1000 ml. Chloroform mixed and 171 g of benzyl chloroformate added dropwise to this solution at about 20 ° C. The mixture is stirred at room temperature for 1 h, washed with water, dilute hydrochloric acid and again with water and dried over sodium sulfate. After evaporation of the solvents in vacuo, 173 g of oil remain. IR (film): 1695 cm- ¹
  • Example 2
    • N-benzyloxycarbonyl-N-undecyl-2-aminoethanol
      analogous to example 1 from:
      • 124 g of 2-undecylaminoethanol
      • 58 g triethylamine
      • 500 ml chloroform
      • 97 g of benzyl chloroformate.
    • Purification by column chromatography (silica gel // hexane / ethyl acetate).
    • Yield: 113 g of oil with IR (film): 1683 cm ^-1
  • Example 3
    • N-benzyloxycarbonyl-N-hexadecyl-2-aminoethanol
      analogous to example 1 from:
      • 71 g of 2-hexadecylaminoethanol
      • 25 g triethylamine
      • 250 ml chloroform
      • 43 g of benzyl chloroformate.
    • Purification by column chromatography (silica gel // chloroform).
    • Yield: 40.2 g of oil with IR (film): 1690 cm- ¹
  • Example 4
    • N-benzyl-N-octadecyl-2-aminoethanol.
    • 40 ml of ethylene oxide cooled with dry ice are added dropwise to a mixture of 65.9 g of N-benzyloctadecylamine and 200 ml of methanol at room temperature within 2 h, the mixture is stirred for a further 3 h, the solvent is stripped off and the residue is purified by column chromatography (silica gel / Chloroform).
    • Yield: 73 g with mp. 31 ° C.
  • Example 5
    • N-benzyloxycarbonyl-N-octadecyl-3-aminopropanol
      analogous to example 1 from:
      • 34.2 g of 3-octadecylamino propanol
      • 10.5 g triethylamine
      • 100 ml chloroform
      • 17.7 g of benzyl chloroformate.
    • Purification by column chromatography (silica gel // chloroform).
    • Yield: 33.1 g of oil with IR (film): 1680 cm- ¹
  • Example 6
    • N-benzyloxycarbonyl-N-octadecyl-4-aminobutanol
      analogous to example 1 from:
      • 24.8 g of 4-octadecylamino-butanol
      • 7.4 g triethylamine
      • 200 ml chloroform
      • 12.5 g benzyl chloroformate.
    • Purification by column chromatography (silica gel / chloroform).
    • Yield: 18 g of oil with IR (film): 1690 cm ^-1
  • Example 7
    • N-benzyloxycarbonyl-N-eicosyl-2-aminoethanol
      analogous to example 1 from:
      • 32.8 2-eicosylaminoethanol
      • 9.7 g triethylamine
      • 200 ml chloroform
      • 16.3 g benzyl chloroformate.
    • Purification by column chromatography (silica gel // hexane / ethyl acetate).
    • Yield: 14.6 g with mp 53-54 ° C, IR (film): 1690 cm ^-1
    • Representation of the phospholipids of formula IV.
  • Example 8
    • N-benzyloxycarbonyl-N-methyl-2-aminoethanol phosphocholine.
      • a) In a mixture of 105 g of dichlorophosphoric acid 2-bromomethyl ester, 53 ml of pyridine and 800 ml of absolute. Chloroform, 46 g of N-benzyloxycarbonyl-N-methyl-2-aminoethanol, dissolved in 220 ml of chloroform, are added dropwise with ice cooling. The reaction mixture is stirred for 1 h while cooling with ice and after adding ice water for a further hour at room temperature. The organic phase is separated off, washed neutral with water, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel / chloroform / methanol).
    • Yield: 28g (N-benzyloxycarbonyl-N-methyl-2-aminoethyl) -2-bromethyl-phosphate (oil).
      • b) 28 g (N-benzyloxycarbonyl-N-methyl-2-aminoethyl) -2-bromethylphosphate are dissolved in 300 ml of dry toluene, 30 ml of 33% ethanolic trimethylamine solution are added and the mixture is stirred in an autoclave at 60 ° C. for 4 h . The solvents are then stripped off on a Rotavapor and the residue is purified by column chromatography (silica gel / chloroform / methanol / water).
    • Yield: 8.5 g with mp. 75-78 ° C.
  • Example 9
    • N-benzyloxycarbonyl-N-undecyl-2-aminoethanol phosphocholine
      analogous to example 8 from:
      • a) 75 g of 2-bromoethyl dichlorophosphate
        • 51 ml pyridine
        • 600 ml chloroform
        • 54.2 g of N-benzyloxycarbonyl-N-undecyl-2-aminoethanol in 150 ml of chloroform.
    • Yield: 47.8 g (N-benzyloxycarbonyl-N-undecyl-2-aminoethyl) -2-bromethyl-phosphate (oil).
      • b) 47.6 g (N-benzyloxycarbonyl-N-undecyl-2-aminoethyl) -2-bromethyl-phosphate.
        • 300 ml toluene
        • 30 ml of 33% ethanolic trimethylamine solution.
    • Yield: 29.9 with mp. 224-226 ° C IR (in KBr): 1692 cm ^-1
  • Example 10
    • N-benzyloxycarbonyl-N-hexadecyl-2-aminoethanol phosphocholine
      analogous to example 8 from:
      • a) 46 g of 2-bromoethyl dichlorophosphate
        • 23 ml pyridine
        • 400 ml chloroform
        • 40 g of N-benzyloxycarbonyl-N-hexadecyl-2-aminoethanol in 95 ml of chloroform.
    • Yield: 21.5 g (N-benzyloxycarbonyl-N-hexadecyl-2-aminoethyl) -2-bromethyl-phosphate (oil).
      • b) 21.4g (N-benzyloxycarbonyl-N-hexadecyl-2-aminoethyl) -2-bromethyl-phosphate
        • 100 ml toluene
        • 10 ml of 33% ethanolic trimethylamine solution.
    • Yield: 7 with mp 226-228 ° C IR (in KBr): 1691 cm ^-1
  • Example 11
    • N-benzyl-N-octadecyl-2-aminoethanol phosphocholine.
      • a) 8.3 g of dichlorophosphoric acid 2-bromoethyl ester are added dropwise to a mixture of 10 g of N-benzyl-N-octadecyl-2-aminoethanol, 50 ml of chloroform and 5 g of triethylamine while cooling with ice. The reaction mixture is stirred for a further 3 h at room temperature and after adding ice water for a further 1 h. The organic phase is separated off, washed neutral with water, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel / chloroform / methanol).
    • Yield: 9.2 g (N-benzyl-N-octadecyl-2-- aminoethyl) -2-bromethylphosphate (oil)
      • b) N-benzyl-N-octadecyl-2-aminoethanol phosphocholine
        • analogous to example 8b from:
        • 9.2 g (N-benzyl-N-octadecyl-2-aminoethyl) -2-bromethyl phosphate
        • 30 ml toluene
        • 5.2 ml of 33% ethanolic trimethylamine solution.
    • Yield: 6.4 g with mp. 215-217 ° C.
  • Example 12
    • N-benzyloxycarbonyl-N-octadecyl-3-aminopropanol (1) phosphocholine
      analogous to example 8 from:
      • a) 34.3 g of 2-bromoethyl dichlorophosphoric ester
        • 140 ml pyridine
        • 140 ml chloroform
        • 32.7 g of N-benzyloxycarbonyl-N-octadecyl-3-aminopropanol in 100 ml of chloroform.
    • Yield: 9.6 g (N-benzyloxycarbonyl-N-octadecyl-3-aminopropyl) -2-bromethyl-phosphate (oil).
      • b) 9.5 g (N-benzyloxycarbonyl-N-octadecyl-3-aminopropyl) -2-bromethyl-phosphate
        • 45 ml toluene
        • 5 ml of 33% ethanolic trimethylamine solution.
    • Yield: 6.5 g with mp 219-223 ° C IR (in KBr): 1688 cm ^-1 .
  • Example 13
    • N-benzyloxycarbonyl-N-octadecyl-4-aminobutanol (1) phosphocholine
      analogous to example 8 from:
      • a) 17.4g dichlorophosphoric acid 2-bromethyl ester
        • 72 ml pyridine
        • 72 ml chloroform
        • 17 g of N-benzyloxycarbonyl-N-octadecyl-4-aminobutanol in 40 ml of chloroform.
    • Yield: 6.1 g (N-benzyloxycarbonyl-N-octadecyl-4-aminobutyl) -2-bromethyl-phosphate (oil).
      • b) 6 g (N-benzyloxycarbonyl-N-octadecyl-4-aminobutyl) -2-bromethyl-phosphate
        • 30 ml toluene
        • 3 ml of 33% ethanolic trimethylamine solution.
    • Yield: 4g with mp. 220 ° C (dec.) IR (in KBr): 1694 cm ^-1 .
  • Example 14
    • N-benzyloxycarbonyl-N-eicosyl-2-aminoethanol phosphocholine
      analogous to example 8 from:
      • a) 14.5 g of dichlorophosphoric acid 2-bromomethyl ester
        • 7.5 ml pyridine
        • 120 ml chloroform
        • 14.5 g of N-benzyloxycarbonyl-N-eicosyl-2-aminoethanol in 30 ml of chloroform.
    • Yield: 12.7 g (N-benzyloxycarbonyl-N-eicosyl-2-aminoethyl) -2-bromethyl-phosphate (oil).
      • b) 12.6 g (N-benzyloxycarbonyl-N-eicosyl-2-aminoethyl) -2-bromethyl-phosphate
        • 60 ml of toluene
        • 20 ml of 33% ethanolic trimethylamine solution.
    • Yield: 1 1.4 g with mp 210 ° C (dec.) IR (in KBr): 1694 cm ^-1 .
  • Example 15
    • (N-benzyl-N-octadecyl-2-aminoethyl) -2-triethylammonioethyl phosphate
      analogous to Example 8b
      • 11.8 g (N-benzyl-N-octadecyl-2-aminoethyl) -2-bromethyl-phosphate
      • 60 ml of toluene
      • 5 ml triethylamine and 10 ml 2-propanol.
    • Yield: 10.2 g with mp. 215-216 ° C.
  • Example 16
    • (N-benzyl-n-octadecyl-2-aminoethyl) -2-dimethylammonioethyl phosphate
      analogous to example 8b from:
      • 11.8g g (N-benzyl-N-octadecyl-2-aminoethyl) -2-bromethyl-phosphate
      • 60 ml toluene and 30 ml 2-propanol
      • 10 ml 40% aqueous dimethylamine solution.
    • Yield: 9.5 g with mp. 210 ° C.
• C. Preparation of the Phospholipids of Formula X
  • Example 17
    • 2-methylaminoethanolphosphocholine.
    • 8 g of N-benzyloxycarbonyl-N-methyl-2-aminoethanol-phosphocholine are dissolved in 60 ml of dioxane and 15 ml of water, the solution is mixed with 0.8 g of 10% palladium / activated carbon and the reaction mixture is hydrogenated with hydrogen. After the H ₂ uptake has ended, the solution is filtered and the filtrate is evaporated to dryness in vacuo.
    • Yield: 5 g of waxy substance.
  • Example 18
    • 2-Undecylamino-ethanol-phosphocholine analogous to Example 17 from:
      • 14g of N-benzyloxycarbonyl-N-undecyl-2-aminoethanol-phosphocholine and
      • 1.4g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 9.2 g with mp. 205-208 ° C.
  • Example 19
    • 2-Hexadecylamino-ethanol-phosphocholine analogous to Example 17 from:
      • 6.9 g of N-benzyloxycarbonyl-N-hexadecyl-2-aminoethanol-phosphocholine and
      • 0.7 g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 5.2 g with mp. 203-207 ° C (dec.).
  • Example 20
    • 2-octadecylamino-ethanol-phosphocholine analogous to Example 17 from:
      • 6.4 g of N-benzyl-N-octadecyl-2-aminoethanol-phosphocholine and
      • 0.6g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 5 g with mp. 210-212 ° C.
  • Example 21
    • 3-octadecylamino-propano-phosphocholine analogous to Example 17 from:
      • 6.2 g of N-benzylocycarbonyl-N-octadecyl-3-aminopropanol-phosphocholine and
      • 0.6g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 4.4 g with mp. 227-229 ° C.
  • Example 22
    • 4-octadecylamino-butanol-phosphocholine analogous to Example 17 from:
      • 3.7 g of N-benzyloxycarbonyl-N-octadecyl-4-aminobutanol-phosphocholine and
      • 0.4g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 2.2 g with mp. 208-210 ° C.
  • Example 23
    • 2-Eicosylamino-ethanol-phosphocholine analogous to Example 17 from:
      • 11 g of N-benzyloxycarbonyl-N-eicosyl-2-aminoethanol-phosphocholine and
      • 1.1 g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 7.4 g with mp. 214-219 ° C.
  • Example 24
    • (N-octadecyl-2-aminoethyl) -2-triethylammonioethyl phosphate
      analogous to example 17 from:
      • 10 g (N-benzyl-N-octadecyl-2-aminoethyl) -2-triethylammonioethyl phosphate and
      • 1 g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 8.1 g with mp. 218-219 ° C.
  • Example 25
    • (N-octadecyl-2-aminoethyl) -2-dimethylam monioethyl phosphate
      analogous to example 17 from:
      • 9.3 g (N-benzyl-N-octadecyl-2-aminoethyl) -2-dimethylammonioethyl phosphate and
      • 0.9 g Pd activated carbon in dioxane / water = 4: 1 (V / V).
    • Yield: 7.5 g with mp 220-223 ° C.
• D. Preparation of the Phospholipids of Formula
  • Example 26
    • 2- (3-ethyl-1-octadecylureido) ethanol phosphocholine.
    • 0.5 g of 2-octadecylaminoethanolphosphocholine are dissolved in 10 ml of chloroform, 0.14 g of ethyl isocyanate and a few drops of dimethylformamide are added to the solution, and the mixture is stirred at room temperature for about 4 hours. The solution is concentrated in vacuo and the residue is purified by column chromatography (silica gel // chloroform / methanoi / water).
    • Yield: 0.43 g with mp. 214-215 ° C IR (in KBr): 1630, 1535 cm ^-1 .
  • Example 27
    • 2- (3-methyl-1-octadecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-octadecylaminoethanol phosphocholine
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.35 g with mp. 219-220 ° C IR (in KBr): 1625.1540 cm ^-1 .
  • Example 28
    • 2- (3-methyl-1-octadecylthioureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-octadecylaminoethanol phosphocholine
      • 0.15 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.41 g with mp. 215-217 ° C.
  • Example 29
    • 2- (3,3-Dimethyl-1-octadecylureido) ethanol phosphocholine.
    • 0.5 g of 2-octadecylaminoethanolphosphocholine are dissolved in 10 ml of chloroform, 0.21 g of dimethylcarbamoyl chloride and 0.14g of silver carbonate are added to the solution and the mixture is stirred for about 12 hours at room temperature. The solution is concentrated in vacuo and the residue is purified by column chromatography (silica gel / chloroform / methanol / water).
    • Yield: 0.31 g with mp. 215-216 ° c IR (in KBr) 1634cm ^-1 .
  • Example 30
    • 2- (3-butyl-1-octadecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-octadecylaminoethanol phosphocholine
      • 0.2 g butyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.38 g with mp. 208-210 ° C IR (in KBr): 1625, 1530 cm ^-1 .
  • Example 31
    • 2- (3-Hexadecyl-1-octadecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-octadecylaminoethanol phosphocholine
      • 0.6 g hexadecyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.63 g with mp 200-203 ° C IR (in KBr): 1625, 1535cm ^-1 .
  • Example 32
    • 2- (3-benzyl-1-octadecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-octadecylaminoethanol phosphocholine
      • 0.27 g benzyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.42 g with mp 221-222 ° C.
  • Example 33
    • 2- (3-methyl-1-undecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.15 g methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.3 g waxy substance with a clear point of ~ 185 ° C
      • IR (in KBr): 1629, 1540 cm ^-1 .
  • Example 34
    • 2- (3-ethyl-1-undecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.18 g of ethyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.3g waxy substance with a clear point ~ 180-183 ° C
      • IR (in KBr): 1626, 1536 cm ^-1 .
  • Example 35
    • 2- (3,3-Dimethyl-1-undecylureido) ethanol phosphocholine
      analogous to example 29 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.28 g dimethyl carbamic acid chloride
      • 0.18 g silver carbonate
      • 10 ml chloroform.
    • Yield: 0.32 waxy substance with clear point: 203-204 ° C
      • IR (in KBr): 1634cm ^-1 .
  • Example 36
    • 2- (3-methyl-1-undecylthioreido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.19 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.33 g waxy substance with a clear point of ~ 165 ° C.
  • Example 37
    • 2- (3-phenyl-1-undecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.31 g phenyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.61 g waxy substance IR (in KBr): 1649.1538 cm ^-1 .
  • Example 38
    • 2- (3-benzyl-1-undecylureido) ethanol phosphocholine
    • analogous to example 26 from:
      • 1.5 g of 2-undecylaminoethanol phosphocholine
      • 1.1 g benzyl isocyanate
      • 30 ml chloroform.
    • Yield: 1.7 g waxy substance IR (in KBr): 1533.1628 cm ^-1 .
  • Example 39
    • 2- (3-Hexadecyl-1-undecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.7 g hexadecyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.69 with mp 196-199 ° C IR (in KBr): 1622.1533 cm- ^i.
  • Example 40
    • 2- (3-oleyl-1-undecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-undecylaminoethanolphosphocholine
      • 0.8 g oleyl isocyanate
      • 10 ml chloroform under nitrogen.
    • Yield: 0.61 g of waxy substance.
  • Example 41
    • 2- (1-Hexadecyl-3-methylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.3 g of 2-hexadecylaminoethanol phosphocholine
      • 0.08 g methyl isocyanate
      • 5 ml chloroform.
    • Yield: 0.22 g with mp. 215-218 ° C IR (in KBr): 1635, 1540 cm ^-1 .
  • Example 42
    • 2- (3-ethyl-1-hexadecylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-hexadecylaminoethanol phosphocholine
      • 0.15 g ethyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.45 g with mp. 213-217 ° C.
  • Example 43
    • 2- (1-Hexadecyl-3-methylthioureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g 2-hexadecylaminoethanol phosphocholine
      • 0.16 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.2 g with mp 210-212 ° C.
  • Example 44
    • 2- (3,3-Dimethyl-1-hexadecylureido) ethanol phosphocholine
      analogous to example 29 from:
      • 0.3 g of 2-hexadecylaminoethanol phosphocholine
      • 0.24 g of dimethyl carbamic acid chloride
      • 0.1 g silver carbonate
      • 5 ml chloroform.
    • Yield: 0.15 g with mp. 208-211 ° C IR (in KBr): 1635 cm ^-1 .
  • Example 45
    • 3- (3-methyl-1-octadecylureido) propanol (1) phosphocholine
      analogous to example 26 from:
      • 0.5 g 3-octadecylamino-propanol- (1) -phosphocholine
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.43 g with mp 221-224 ° C IR (in KBr): 1628.1540 cm- ^i.
  • Example 46
    • 3- (3-ethyl-1-octadecyiureido) propanol (1) phosphocholine
      analogous to example 26 from:
      • 0.5 g 3-octadecylamino-propanol- (1) -phosphocholine
      • 0.14 g of ethyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.3 g with mp. 215-218 ° C IR (in KBr): 1626, 1535cm ^-1 .
  • Example 47
    • 3- (3,3-Dimethyl-1-octadecylureido) propanol (1) phosphocholine
      analogous to example 29 from:
      • 0.5 g 3-octadecylamino-propanol- (1) -phosphocholine
      • 0.18 g dimethyl carbamic acid chloride
      • 0.14 g of silver carbonate
      • 10 ml chloroform.
    • Yield: 0.28 g with mp. 224-225 ° C IR (in KBr): 1633 cm ^-1 .
  • Example 48
    • 3- (3-methyl-1-octadecylthioureido) propanol (1) phosphocholine
      analogous to example 26 from:
      • 0.5 g 3-octadecylamino-propanol- (1) -phosphocholine
      • 0.15 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.36 g with mp 210-212 ° C.
  • Example 49
    • 4- (3-methyl-1-octadecylureido) butanol (1) phosphocholine
      analogous to example 26 from:
      • 0.5 g of 4-octadecylamino-butanol (1) phosphocholine
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.4 g with mp 226-230 ° C IR (in KBr): 1629.1541 cm ^-1 .
  • Example 50
    • 4- (3-ethyl-1-octadecylureido) butanol (1) phosphocholine
      analogous to example 26 from:
      • 0.3 g of 4-octadecylamino-butanol (1) phosphocholine
      • 0.1 g ethyl isocyanate
      • 5 ml chloroform.
    • Yield: 0.25 g with mp. 215-216 ° C IR (in KBr): 1623, 1532cm ^-1 .
  • Example 51
    • 4- (3,3-dimethyl-1-octadecyl) butanol (1) phosphocholine
      ananolg Example 29 from:
      • 0.3 g of 4-oxadecylamino-butanol (1) phosphocholine
      • 0.13 g of dimethyl carbamic acid chloride
      • 0.1 g silver carbonate
      • 5 ml chloroform.
    • Yield: 0.15 g with mp. 234-236 ° C IR (in KBr): 1632 cm- '.
  • Example 52
    • 4- (3-methyl-1-octadecylthioureido) butanol (1) phosphocholine
      analogous to example 26 from:
      • 0.3 g of 4-octadecylamino-butanol (1) phosphocholine
      • 0.1 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.21 g with mp 221-224 ° C.
  • Example 53
    • 2- (1-eicosyl-3-methylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-eicosylaminoethanolphosphocholine
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.35 g with mp. 222-224 ° C.
  • Example 54
    • 2- (1-eicosyl-3-ethylureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-eicosylaminoethanolphosphocholine
      • 0.14g ethyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.4 g with mp. 218-220 ° C.
  • Example 55
    • 2- (3,3-Dimethyl-1-eicosylureido) ethanol phosphocholine
      analogous to example 29 from:
      • 0.5 g of 2-eicosylaminoethanolphosphocholine
      • 0.21 g of dimethyl carbamic acid chloride
      • 0.14g silver carbonate
      • 10 ml chloroform.
    • Yield: 0.3 g with mp. 215-217 ° C.
  • Example 56
    • 2- (1-eicosyl-3-methylthioureido) ethanol phosphocholine
      analogous to example 26 from:
      • 0.5 g of 2-eicosylaminoethanolphosphocholine
      • 0.15 g methyl isothiocyanate
      • 10 ml chloroform.
    • Yield: 0.3 g with mp 210-211 ° C.
  • Example 57
    • 2- (1-undecylureido) ethanol-phosphocholine analogous to Example 17 from:
      • 1.2 g of 2- (3-benzyl-1-undecylureida) ethanol phosphocholine and
      • 0.72 g Pd activated carbon, which are added in 6 portions within 20 h, in dioxane / water = 4: 1 (V / V).
    • Yield: 0.5 g waxy substance IR (in KBr): 1652.1597 cm- ¹ .
  • Example 58
    • [2- (3-methyl-1-octadecylureido) ethyl] - (2-triethylammonioethyl) phosphate
      analogous to example 26 from:
      • 0.5 g (N-octadecyl-2-aminoethyl) -2-triethylam monioethyl phosphate
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform,
    • Yield: 0.41 g with mp. 220-221 ° C.
  • Example 59
    • [2- (3-methyl-1-octadecylureido) ethyl] - (2-dimethylammonioethyl) phosphate
      analogous to example 26 from:
      • 0.5 g (N-octadecyl-2-aminoethyl) -2-dimethylam monioethyl phosphate
      • 0.11 g of methyl isocyanate
      • 10 ml chloroform.
    • Yield: 0.35 g with mp. 215-216 ° C.
  • Example 60
    • 2- (3-nexadecyl-1-methylureido) ethanol phosphocholine.
    • 0.5 g of 2-methylamino-ethanol-phosphocholine are dissolved in 10 ml of N-methylacetamide, the solution is mixed with 1.08 g of hexadecyl isocyanate and stirred for 24 hours at room temperature. The solution is concentrated in vacuo and the residue by column chromatography (silica gel // chloroform / methanol / water)
    • cleaned.
    • Yield: 0.3 g with mp 210-213 ° C.
    • The following are prepared as in Example 60:
      • 2- (1-methyl-3-octadecylureido) ethanol phosphocholine
      • 2- (3-eicosyl-1-methylureido) ethanol phosphocholine
      • 2- (1-methyl-3-oleylureido) ethanol phosphocholine
  • Example 61
    • N-methoxycarbonyl-N-octadecyl-2-aminoethanol (1) phosphocholine.
    • 50 mg of N-octadecyl-2-aminoethanol- (1) -phosphocholine are dissolved in 2 ml of chloroform, 20mg methyl chloroformate and 5 drops triethylamine added. The mixture is stirred for one hour at room temperature, concentrated in vacuo and the residue is purified by column chromatography (silica gel // chloroform / methanol / water).
    • Yield: 41 mg of waxy substance IR (in KBr): 1692 cm ^-1 .
  • Example 62
    • N-ethoxycarbonyl-N-octadecyl-2-aminoethanol (1) phosphocholine
      anaolg example 61 from:
      • 50 mg of N-octadecyl-2-aminoethanol (1) phosphocholine
      • 20 mg ethyl chloroformate
      • 5 drops of triethylamine
      • in 2 ml chloroform.
    • Yield: 39 mg of waxy substance IR (in KBr): 1690 cm ^-1 .
  • Example 63
    • N-Benzyloxycarbonyl-N-octadecyl-2-aminoethanol- (1) -phosphocholine analogously to Example 61 from:
      • 50 mg of N-octadecyl-2-aminoethanol (1) phosphocholine
      • 34 mg benzyl chloroformate
      • 5 drops of triethylamine
      • in 2 ml chloroform.
    • Yield: 55 mg with mp. 211 ° C.

Claims (18)

1. Substituted aminoalkanol phospholipids of the general formula I

in which

X represents an oxygen or a sulphur atom and

Y the radical-NR¹R² or-OR³,

wherein

R¹, R² can be the same or different and represent a saturated or unsaturated straight-chained ε branched alkyl radical having 1 to 20 carbon at oms, a benzyl radical, a phenyl radical or hydro gen,

R³ represents phenyl, benzyl or C_1-4-alkyl,

R⁴, R⁵, R⁶ can be the same or different and re present hydrogen or a low alkyl radical having to 4 carbon atoms,

I represents an integerfrom 0 to 19,

m represents an integer from 2 to 6,

n represents an integer from 2 to 4.

2. Substituted aminoalkanol phospholipids according to claim 1 in which

X represents an oxygen or a sulphur atom and

Y the radical-NR¹R²,

wherein

R¹, R² can be the same or different and represent a saturated or an unsaturated, straight-chained or branched alkyl radical having 1 to 20 carbon atoms, a benzyl radical, a phenyl radical or hydrogen,

R⁴, R⁵, R6 can be the same or different and represent hydrogen or a low alkyl radical having 1 to 4 carbon atoms,

I represents an integer from 0 to 19,

m represents an integer from 2 to 6, and

n represents an integer from 2 to 4.

3. Substituted aminoalkanol phosphocholines according to claim 1, in which

X represents an oxygen or a sulphur atom and

Y the radical NR¹R²,

wherein

R¹, R² can be the same or different and represent an alkyl radical having 1 to 20 carbon atoms, R4, R5, R⁶ each represent a methyl group,

I an integer from 0 to 19,

m an integer from 2 to 6, and

n represents 2.

4. Substituted aminoalkanol phospholipids according to claim 1, in which

X represents an oxygen atom and

Y the radical -OR3,

wherein

R³ represents phenyl, benzyl or C_1-4-alkyl,

R4, R5, R6 can be the same or different and represent hydrogen or a low alkyl radical having 1 to 4 carbon atoms,

I represents an integer from 0 to 19,

m an integer from 2 to 6, and

n an integerfrom 2 to 4.

5. Substituted aminoalkanol phosphocholines according to claim 1, in which

X represents an oxygen atom and

Y the radical -OR³,

wherein

R³ represents benzyl or C_1-4-alkyl,

R4, R5, R6 each represent a methyl group,

I represents an integer from 0to 19,

m an integer from 2to 6, and

n represents 2.

6. A method of producing compounds according to any of claims 1 to 3, in which compounds of the general formula X

wherein R⁴, R⁵, R⁶, I, m, n represent the same as in formula I, are reacted in a manner known per se with carbonic acid derivatives of formula XI or XII

wherein R¹, R², X represent the same as in Formula I, with or without the presence of an inert organic solvent, possibly with the addition of a catalyst or of an auxiliary base, in particular when compounds of formula XII are used.

7. A method of producing compounds according to any of claims 1 to 3, in which N-alkyl-aminoalkanols of the general formula II

are reacted with benzyl halides or chloroformic acid benzyl esters to form compounds of formula III

wherein R⁷ represents a radical which may be separated by hydrogenation such as, for exem- ple, benzyl or benzyloxy carbonyl, and the compounds III are phosphorylated according to processes known per se by reacting with dichlorophosphoric acid-ω-alkyl halide esters and then converted by reacting with amines NR⁴R⁵R⁶ to form the compounds of formula IV

which are hydrogenated according to methods known per se to form the compounds of formula X and are reacted with the carbonic acid derivatives of formula XI or XII.

8. A method of producing compounds according to any of claims 1 to 3 in which R¹ = R² = H and X = 0 in formula I, in which compounds of formula I in which R¹ = benzyl, R² = H and X = 0, are hydrogenated in an inert organic solvent in the presence of a conventional hydrogenation catalyst.

9. A method of producing compounds of formula X according to claim 6, in which compounds offormula IV

wherein R⁴, R⁵, R6, I, m, n represent the same as in formula I and R⁷ represents a radical separable by hydrogenation, such as, for example, benzyl or benzyloxy carbonyl, are hydrogenated in an inert organic solvent with the use of a conventional hydrogenation catalyst.

10. A method for producing compounds of formula IV according to claim 7, in which N,N-disubstituted aminoalkanols of formula III

in which I, m and R⁷ represent the same as in formula IV, are phosphorylated with a dichlorophosphoric acid-ω-alkyl halide ester of formula V

wherein n represents the same as in formula I and Hal represents a chlorine or a bromine atom, in an inert organic solvent, optionally with the use of an auxiliary base, and then reacting the products with an amine of formula VI

wherein R⁴, R⁵, R⁶ are the same as in formula I, in an inert organic solvent, optionally under pressure.

11. A method of producing compounds of formula IV according to claim 7, in which compounds of formula III according to claim 10 are phosphorylated with phosphorus oxytrichloride and then allow the product to react with an alkane diol of formula VII

in which n is the same as in formula I, possibly with the introduction of auxiliary bases and inert solvents to form the cyclic phosphor compounds of formula VIII

in which I, m, n represent the same as in formula I and R⁷ represents the same as in formula IV, and to then allow the compounds of formula VIII to react with an amine of formula VI according to claim 10 in an organic solvent, optionally under pressure.

12. A method of producing compounds fo formula VIII according to claim 11, in which compounds of formula III according to claim 10 are reacted with a cyclic phosphor compound of formula IX

wherein n represents the same as in formula I, in an inert organic solvent with the addition of an auxiliary base.

13. A method of producing compounds of formula III according to claim 10, in which N-alkylamino alkanols of formula II

wherein I and m are the same as in formula I are reacted with a benzyl halide or a chloroformic acid benzyl ester in an inert organic medium, optionally with the addition of an auxiliary base.

14. A method of producing compounds according to any of claims 1, 4 and 5, in which disubstituted amino alcohols of formula XIII

wherein R³, l and m are the same as in formula I, are phosphorylated with a dichlorophosphoric acid-ω-alkyl halide ester of formula V according to claim 10 in an inert organic solvent, optionally with the use of an auxiliary base, and the product is then reacted with an amine of formula VI according to claim 10 in an inert organic solvent, optionally under pressure.

15. A method of producing compounds according to any of claims 1,4 and 5, in which compounds of formula XIII according to claim 14 are converted by phosphorylation with phosphorus oxytrichloride and subsequent reaction with an alkane diol of formula VII according to claim 11 optionally with the introduction of auxiliary bases and inert solvents, to the cyclic phosphor compounds of formula XIV

wherein R³, I, m and n are the same as in formula I, and the compound XIV is subsequently allowed to react with an amine of formula VI according to claim 10 in an organic solvent, optionally under pressure.

16. A method of producing compounds according to any of claims 1, 4 and 5, in which compounds of formula XIII according to claim 14 are reacted with cyclic phosphor compounds of formula IX according to claim 12 in an inert organic solvent with the addition of an auxiliary base.

17. A method of producing compounds of formula XIII according to claim 14, in which N-alkylamino alkanols of formula II according to claim 7 are reacted with chloroformic acid esters in an inert organic medium, optionally with the addition of an auxiliary base.

18. Amethod of producing compounds according to any of claims 1, 4 and 5, wherein amino alkanol phospholipids of formula X according to claim 6 are reacted with chloroformic acid esters in an inert organic medium, optionally with the addition of an auxiliary base.